Structural Biochemistry/Proteins/Internal Ribosome Entry Sites

IRES
Eukaryotic translation initiation occurs through a cap mediated mechanism where eIF4E recruits the 5’ capped mRNA to the small subunit. It was discovered in viruses that another mechanism exists through the use of internal ribosome entry sites (IRESs). The IRES is a segment of DNA that allows for translation initiation in the middle of a messenger RNA bypassing the 5’ cap dependent system.

History
They were first discovered by Nahum Sonenberg and Eckard Wimmer in 1988 in Poliovirus RNA and encephalomyocarditis virus RNA. They are located mostly in the 5’ UTR of RNA viruses and allow for cap independent RNA translation. This is useful for the virus because it ensures that viral mRNA is still translated even when host cell translation is shut off. Poliovirus secretes a viral protease that cleaves the eIF4E complex and inhibits cap dependent translation while translating its own mRNA through IRESs.

Mechanism
The mechanism of viral IRES function varies depending on the virus. Hepatitis C virus does not require scanning for the initiator codon because its IRES directly binds to the 40S subunit in a way that the initiator codon is already in the P site. They also do not require any eukaryotic initiation factors. Picornavirus IRESs do not bind directly to the small subunit but rather to the eIF4G and require additional proteins know as IRES trans acting factors (ITAF) to function.